Breast cancer remains a leading cause of cancer-related deaths among women globally, necessitating the development of more effective therapeutic agents with minimal side effects. This study explores novel 1,2,4-triazine-3(2H)-one derivatives as potential inhibitors of Tubulin, a pivotal protein in cancer cell division, highlighting a targeted approach in cancer therapy. Using an integrated computational approach, we combined quantitative structure–activity relationship (QSAR) modeling, ADMET profiling, molecular docking, and molecular dynamics simulations to evaluate and predict the efficacy and stability of these compounds. Our QSAR models, developed through rigorous statistical analysis, revealed that descriptors such as absolute electronegativity and water solubility significantly influence inhibitory activity, achieving a predictive accuracy (R²) of 0.849. Molecular docking studies identified compounds with high binding affinities, particularly Pred28, which exhibited the best docking score of − 9.6 kcal/mol. Molecular dynamics simulations conducted over 100 ns provided further insights into the stability of these interactions. Pred28 demonstrated notable stability, with the lowest root mean square deviation (RMSD) of 0.29 nm and root mean square fluctuation (RMSF) values indicative of a tightly bound conformation to Tubulin. The novelty of this work lies in its methodological rigor and the integration of multiple advanced computational techniques to pinpoint compounds with promising therapeutic potential. Our findings advance the current understanding of Tubulin inhibitors and open avenues for the synthesis and experimental validation of these compounds, aiming to offer new solutions for breast cancer treatment.

乳腺癌仍然是全球女性癌症相关死亡的主要原因，因此需要开发更有效、副作用最小的治疗药物。这项研究探索了新型 1,2,4-三嗪-3(2H)-one 衍生物作为微管蛋白（癌细胞分裂中的关键蛋白）的潜在抑制剂，突出了癌症治疗的靶向方法。我们使用集成计算方法，结合定量构效关系 (QSAR) 建模、ADMET 分析、分子对接和分子动力学模拟来评估和预测这些化合物的功效和稳定性。我们通过严格的统计分析开发的 QSAR 模型表明，绝对电负性和水溶性等描述符会显着影响抑制活性，预测精度 (R ² ) 为 0.849。分子对接研究发现了具有高结合亲和力的化合物，特别是 Pred28，其表现出最佳对接分数 - 9.6 kcal/mol。进行超过 100 纳秒的分子动力学模拟可以进一步了解这些相互作用的稳定性。 Pred28 表现出显着的稳定性，最低均方根偏差 (RMSD) 为 0.29 nm，均方根波动 (RMSF) 值表明与微管蛋白紧密结合的构象。这项工作的新颖性在于其方法论的严谨性以及多种先进计算技术的整合，以查明具有良好治疗潜力的化合物。我们的研究结果推进了目前对微管蛋白抑制剂的理解，并为这些化合物的合成和实验验证开辟了途径，旨在为乳腺癌治疗提供新的解决方案。